Project Summary: An estimated 60% of medical cannabis patients report concomitant use of prescription opioids to alleviate pain, yet there is an enormous gap in our understanding of how the drug combination impacts opioid abuse liability and analgesic effectiveness. Studies in our laboratory have demonstrated that cannabis (1) produces dose-related increases in analgesia measured with the Cold Pressor Test (CPT), a reliable and validated pain induction technique that has predictive validity for analgesics that are used for chronic pain, and (2) enhances the analgesic effects of a sub-threshold analgesic dose of the popularly prescribed opioid, oxycodone (OXY; 2.5 mg) without increasing cannabis?s abuse liability. However, these studies did not directly assess the impact of the combination on oxycodone?s abuse liability, a critical public health concern given the rising rates of prescription opioid abuse. Furthermore, the cannabis used previously had negligible concentrations of cannabidiol (CBD), a non-intoxicating cannabinoid that is hypothesized to decrease the abuse liability of tetrahydrocannabinol (THC), the primary psychoactive component of cannabis, and opioids. CBD is also hypothesized to alleviate chronic (neuropathic) pain. Despite the widespread medical use and availability of cannabis with varying THC:CBD ratios, no studies have assessed how cannabis with varying ratios of THC:CBD affects cannabis?s abuse liability or analgesia when administered alone, or opioid abuse liability and analgesia when given in combination. The proposed study would be the first examination of the abuse liability and analgesic effectiveness of vaporized cannabis with high (~30:1) equal (~1:1) and low (~1:30) THC:CBD ratios, a route of administration and THC:CBD ratios that are ecologically relevant. Healthy cannabis users (N=20, 10M, 10F) with limited opioid experience will complete 8 outpatient laboratory sessions, during which they will be administered a sub- threshold analgesic dose of OXY (2.5 mg) or placebo, followed by inhalations of 30:1, 1:1, 1:30 THC:CBD, or placebo cannabis vapor via Volcano vaporizers. The 30:1 dose will match the 1:1 dose on total THC content, but contain < 1 mg of CBD; the 1:30 dose will match the 1:1 dose on total CBD content, but contain < 1 mg THC. This design allows us to examine the independent and combined effects of THC and CBD on measures of abuse liability (positive subjective effects, self-administration) and analgesia when administered alone and when combined with OXY. Reducing the therapeutic dose and abuse liability of RxOPs while effectively treating pain is a public health priority. Cannabinoids hold promise, but there is an alarming absence of scientific data to inform if they mitigate or enhance adverse effects. The proposed study would provide urgently needed data on the effects of THC and CBD on abuse liability, therapeutic utility of medical cannabis and cannabinoids for chronic pain, and their effects when combined with RxOPs.